CCK-1 receptor modulators

ABSTRACT

Certain imidazole compounds are CCK1 modulators useful in the treatment of CCK1 mediated diseases.

This application is a divisional of non-provisional application, U.S.Ser. No. 11/018,049, filed Dec. 21, 2004, now U.S. Pat. No. 7,250,434which claims priority of provisional application, U.S. Ser. No.60/531,795, filed Dec. 22, 2003. The complete disclosures of theaforementioned related U.S. patent applications are hereby incorporatedherein by reference for all purposes.

This invention relates to CCK-1 receptor modulators for the treatment ofgastrointestinal and CNS disorders. More particularly, this inventionrelates to certain imidazole compounds useful as selective agonists orantagonists of the CCK-1 receptor.

BACKGROUND OF THE INVENTION

Cholecystokinin (CCK) is a brain-gut peptide hormone located both in thegastrointestinal system and in the central nervous system. The actionsof CCK are mediated by two G-protein coupled receptors: CCK-1 (formerlyCCK-A) and CCK-2 (formerly CCK-B/gastrin). These CCK receptors areexpressed throughout the gastrointestinal system and in different partsof the central nervous system including the cortex, the striatum, thehypothalamus, the hippocampus, the olfactory bulb, the vagal afferentneurones, in different enteric nerves, and in the genital tract.

CCK has a number of biological actions. CCK is the primary hormonalregulator of gall bladder contraction in response to a meal. CCKstimulates pancreatic and biliary secretions and regulates GI motilityand specifically gut and colonic motility. CCK promotes proteinsynthesis and cell growth, especially in the GI system and in thepancreas. CCK is involved in mediating satiety after a meal. CCK is animportant neuromodulator and neurotransmitter involved in anxiety andpanic disorder. CCK modulates the release of dopamine. CCK is also knownto antagonize morphine and beta-endorphine induced analgesia and theaction on nociception. A review of CCK receptors, ligands and theactivities thereof may be found in P. de Tullio et al., Exp. Opin.Invest. Drugs 2000, 9(1):129-146.

A number of CCK-1 receptor antagonists are presently in clinical trialsincluding, tarazepide, devazepide and lintitript. Phase III equivalenttrials are in progress by Rotta Research Group and Forest Laboratorieson dexloxiglumide, a CCK-1 antagonist for the treatment of constipation,irritable bowel syndrome and non-ulcer dyspepsia.

Also, Kaken Pharmaceuticals and Mitsubishi-Tokyo Pharmaceuticals areawaiting registration in Japan on loxiglumide, a CCK-1 receptorantagonist for the treatment of GI cancers and pancreatitis. Loxiglumideis the racemate of dexloxiglumide.

A number of CCK-1 receptor agonists are under preclinical investigation.Glaxo Smith Kline, Inc. is investigating GW 5823, GW 7854, GW 7178 andGW 8573, 1,5-benzodiaepines for the treatment of gallstones,gastrointestinal disease and obesity.

Also, Pfizer is investigating the CCK-1 receptor agonist, PD 170292, forobesity.

In Patent application WO 01/85723 there are disclosed certain imidazolesfor the inhibition of gastrin and cholecystokinin receptor ligands ofthe general formula:

In Patent application WO 01/66539 there are disclosed certain imidazolesfor the inhibition of raf kinases for the treatment of cancers of thegeneral formula:

These compounds are not taught as inhibitors of CCK receptors.

Applicants have now discovered that certain imidazoles as describedbelow are useful CCK-1 receptor modulators, agonists and antagonists,and most particularly antagonists. As such, these compounds are usefulto treat a number of disease states mediated by CCK.

SUMMARY OF THE INVENTION

There is provided by the present invention a CCK-1 receptor modulatorhaving the general formula:

wherein,

-   R¹ and R² can be the same or different and are selected from the    group consisting of;    -   a) phenyl, optionally mono-, di- or tri-substituted with R^(p)        or di-substituted on adjacent carbons with —OC₁₋₄alkyleneO—,        —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)- or        —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;        -   R^(p) is selected from the group consisting of —OH,            —C₁₋₆alkyl, —OC₁₋₆alkyl, phenyl, —Ophenyl, benzyl, —Obenzyl,            —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, —CN, —NO₂, —N(R^(y))R^(z)            (wherein R^(y) and R^(z) are independently selected from —H,            —C₁₋₆alkyl or —C₁₋₆alkenyl, or R^(y) and R^(z) may be taken            together with the nitrogen of attachment to form an            otherwise aliphatic hydrocarbon ring, said ring having 4 to            7 members, optionally having one carbon replaced with >O,            ═N—, >NH or >N(C₁₋₄alkyl), optionally having one carbon            substituted with —OH, and optionally having one or two            double bonds in the ring), —(C═O)N(R^(y))R^(z),            —(N—R^(t))COR^(t), —(N—R^(t))SO₂C₁₋₆alkyl (wherein R^(t) is            —H or —C₁₋₆alkyl or two R^(t) in the same substituent may be            taken together with the amide of attachment to form an            otherwise aliphatic hydrocarbon ring, said ring having 4 to            6 members), —(C═O)C₁₋₆alkyl, —(S═(O)_(n))—C₁₋₆alkyl (wherein            n is selected from 0, 1 or 2), —SO₂N(R^(y))R^(z), —SCF₃,            halo, —CF₃, —OCF₃, —COOH and —COOC₁₋₆alkyl;    -   b) phenyl or pyridyl fused at two adjacent ring members to a        three membered hydrocarbon moiety to form a fused five membered        aromatic ring, which moiety has one carbon atom replaced        by >O, >S, >NH or >N(C₁₋₄alkyl) and which moiety has up to one        additional carbon atom optionally replaced by N, the fused rings        optionally mono-, di- or tri-substituted with R^(p);    -   c) phenyl fused at two adjacent ring members to a four membered        hydrocarbon moiety to form a fused six membered aromatic ring,        which moiety has one or two carbon atoms replaced by N, the        fused rings optionally mono-, di- or tri-substituted with R^(p);    -   d) naphthyl, optionally mono-, di- or tri-substituted with        R^(p);    -   e) a monocyclic aromatic hydrocarbon group having five ring        atoms, having a carbon atom which is the point of attachment,        having one carbon atom replaced by >O, >S, >NH or >N(C₁₋₄alkyl),        having up to one additional carbon atoms optionally replaced by        N, optionally mono- or di-substituted with R^(p) and optionally        benzo fused, where the benzo fused moiety is optionally mono-,        di- or tri-substituted with R^(p); and    -   f) a monocyclic aromatic hydrocarbon group having six ring        atoms, having a carbon atom which is the point of attachment,        having one or two carbon atoms replaced by N, having one N        optionally oxidized to the N-oxide, optionally mono- or        di-substituted with R^(p) and optionally benzo fused, where the        benzo fused moiety is optionally mono- or di-substituted with        R^(p);-   R³ is selected from the group consisting of —H and —C₁₋₆alkyl;-   m is selected from 0, 1, or 2;-   Ar is selected from the group consisting of:    -   A) phenyl, optionally mono-, di- or tri-substituted with R^(r)        or di-substituted on adjacent carbons with —OC₁₋₄alkyleneO—,        —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)- or        —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;        -   R^(r) is selected from the group consisting of —OH,            —C₁₋₆alkyl, —OC₁₋₁₆alkyl, phenyl, —Ophenyl, benzyl,            —Obenzyl, —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, —CN, —NO₂,            —N(R^(a))R^(b) (wherein R^(a) and R^(b) are independently            selected from —H, —C₁₋₆alkyl or —C₁₋₆alkenyl, or R^(a) and            R^(b) may be taken together with the nitrogen of attachment            to form an otherwise aliphatic hydrocarbon ring, said ring            having 4 to 7 members, optionally having one carbon replaced            with >O, ═N—, >NH or >N(C₁₋₄alkyl), optionally having one            carbon substituted with —OH, and optionally having one or            two double bonds in the ring), —(C═O)N(R^(a))R^(b),            —(N—R^(c))COR^(c), —(N—R^(c))SO₂C₁₋₆alkyl (wherein R^(c) is            H or C₁₋₆alkyl or two R^(c) in the same substituent may be            taken together with the amide of attachment to form an            otherwise aliphatic hydrocarbon ring, said ring having 4 to            6 members), —(C═O)C₁₋₆alkyl, —(S═(O)_(q))—C₁₋₁₆alkyl            (wherein q is selected from 0, 1 or 2), —SO₂N(R^(a))R^(b),            —SCF₃, halo, —CF₃, —OCF₃, and —COOC₁₋₁₆alkyl;    -   B) phenyl or pyridyl fused at two adjacent ring members to a        three membered hydrocarbon moiety to form a fused five membered        aromatic ring, which moiety has one carbon atom replaced        by >O, >S, >NH or >N(C₁₋₄alkyl) and which moiety has up to one        additional carbon atom optionally replaced by N, the fused rings        optionally mono-, di- or tri-substituted with R^(r);    -   C) phenyl fused at two adjacent ring members to a four membered        hydrocarbon moiety to form a fused six membered aromatic ring,        which moiety has one or two carbon atoms replaced by N, the        fused rings optionally mono-, di- or tri-substituted with R^(r);    -   D) naphthyl, optionally mono-, di- or tri-substituted with        R^(r);    -   E) a monocyclic aromatic hydrocarbon group having five ring        atoms, having a carbon atom which is the point of attachment,        having one carbon atom replaced by >O, >S, >NH or >N(C₁₋₄alkyl),        having up to one additional carbon atoms optionally replaced by        N, optionally mono- or di-substituted with R^(r) and optionally        benzo fused on the condition that two or fewer of said carbon        ring atoms are replaced by a heteroatom, where the benzo fused        moiety is optionally mono-, di- or tri-substituted with R^(r);        and    -   F) a monocyclic aromatic hydrocarbon group having six ring        atoms, having a carbon atom which is the point of attachment,        having one or two carbon atoms replaced by N, optionally mono-        or di-substituted with R^(r) and optionally benzo fused, where        the benzo fused moiety is optionally mono- or di-substituted        with R^(r);-   R⁴ is selected from the group consisting of;    -   I)—COOR⁵, where R⁵ is selected from the group consisting of —H        and —C₁₋₄alkyl, and    -   II) —CONR⁶R⁷, where R⁶ and R⁷ are independently selected from        the group consisting of —H, —C₁₋₆alkyl and —C₃₋₆cycloalkyl        optionally hydroxy substituted, or R⁶ and R⁷ may be taken        together with the nitrogen of attachment to form an otherwise        aliphatic hydrocarbon ring, said ring having 5 to 7 members,        optionally having one carbon replaced with >O, ═N—, >NH or        >N(C₁₋₄alkyl) and optionally having one or two double bonds in        the ring;        and enantiomers, diastereomers, hydrates, solvates and        pharmaceutically acceptable salts, esters and amides thereof.

DETAILED DESCRIPTION OF THE INVENTION

Preferably R¹ and R², optionally substituted as described above, areselected from the group consisting of:

-   -   a) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,        7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,        7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4,5,6 or 7-yl,        1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,    -   b) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or        7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or        7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or        7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,        imidazo[1,2-a]pyridin-5,6,7 or 8-yl,        pyrazolo[1,5-a]pyridin-4,5,6 or 7-yl,        1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,        1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,        1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl,        1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,    -   c) 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or 8-quinolinyl,        5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or 8-quinazolinyl,    -   d) naphthyl,    -   e) furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl,        isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 3-indoxazinyl,        2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl,        2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, or        3-indazolyl,    -   f) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl,        pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or 4-quinolinyl,        2- or 3-quinoxalinyl, 2- or 4-quinazolinyl, and        1-oxy-pyridin-2,3, or 4-yl.

Most preferably R¹ and R² can be the same or different and optionallysubstituted as described above, and are selected from the groupconsisting of phenyl, pyridinyl, and naphthyl. Specific R¹ and R² areselected from the group consisting of phenyl, 2-methoxy-phenyl,3-methoxy-phenyl, 4-methoxy-phenyl, 2,3-dimethoxy-phenyl,2,4-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 2-chloro-phenyl,3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichloro-phenyl,2,4-dichloro-phenyl, 3,4-dichlorophenyl, 2,5-dichloro-phenyl,2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-methyl-phenyl,3-methyl-phenyl, 4-methyl-phenyl, 2,5-dimethyl-phenyl,2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 3-trifluoromethoxy-phenyl,4-trifluoromethoxy-phenyl, 4-t-butyl-phenyl, naphthalen-2-yl,naphthalen-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,4-methanesulfonyl-phenyl, 4-isopropyl-phenyl, 4-ethoxy-phenyl,4-hydroxy-phenyl, benzo[1,3]diox-5-yl, and 2,3-dihydrobenzo[1,4]dioxin-6-yl.

Preferably R^(p) is selected from the group consisting of —OH, —CH₃,—CH₂CH₃, i-propyl, t-butyl, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, phenyl,—Ophenyl, benzyl, —Obenzyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, —Ocyclopentyl, —Ocyclohexyl, —CN, —NO₂, —NH₂, —NHCH₃,—NHCH₂CH₃, —NH(CH₂CH₂CH₃), —NH(CH(CH₃)CH₂CH₃), —NH(allyl),—NH(CH₂(CH₃)₂), —N(CH₃)₂, —N(CH₂CH₃)₂, —NCH₃(CH₂CH₂CH₃), —NCH₃(CH₂CH₃),—NCH₃(CH(CH₃)₂), pyrrolidin-2-on-1-yl, azetidinyl, piperidin-1-yl, 2- or3-pyrrolin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl,pyrrolidin-1-yl, homopiperidin-1-yl, —C(O)NH₂, —C(O)N(CH₃)₂,—C(O)NH(CH₃), —NH(CO)H, —NHCOCH₃, —NCH₃(CO)H, —NCH₃COCH₃, —NHSO₂CH₃,—NCH₃SO₂CH₃, —C(O)CH₃, —SOCH₃, —SO₂CH₃, —SO₂NH₂, —SO₂NHCH₃, —SO₂N(CH₃)₂,—SCF₃, —F, —Cl, —Br, —I, —CF₃, —OCF₃, —COOH, —COOCH₃, and —COOCH₂CH₃.

Most preferably R^(p) is selected from the group consisting of —CH₃,—OCH₃, —OCH₂CH₃, —Cl, —F, —CF₃, —OCF₃, t-butyl, —SO₂CH₃, i-propyl and—OH.

Preferably R³ is selected from the group consisting of —H, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, and —CH(CH₃)₂.

Most preferably R³ is —H or —CH₃.

Preferably m is 0.

In one preferred embodiment of the invention, the Ar attached carbon issaturated and has the configuration

In one more preferred embodiment of the invention, the Ar attachedcarbon is saturated and has the configuration

In another preferred embodiment of the present invention, the Arattached carbon is unsaturated and has the configuration

In another more preferred embodiment of the present invention, the Arattached carbon is unsaturated and has the configuration

Preferably Ar, optionally substituted as described above, is selectedfrom the group consisting of:

-   -   A) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,        7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,        7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4,5,6 or 7-yl,        1,2,3,4-tetrahydro-isoquinolin-4, 5, 6 or 7-yl,    -   B) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or        7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or        7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or        7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,        imidazo[1,2-a]pyridin-5,6,7 or 8-yl,        pyrazolo[1,5-a]pyridin-4,5,6 or 7-yl,        1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,        1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,        1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl,        1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,    -   C) 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or 8-quinolinyl,        5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or 8-quinazolinyl,    -   D) naphthyl,    -   E) furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl,        isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 3-indoxazinyl,        2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl,        2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, or        3-indazolyl,    -   F) pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1-, 3- or        4-isoquinolinyl, 2-, 3- or 4-quinolinyl, 2- or 3-quinoxalinyl,        2- or 4-quinazolinyl.

More preferably Ar, optionally substituted as described above, isselected from the group consisting of phenyl, naphthyl, benzofuran-3-yl,4-, 5-, 6- or 7-benzothiophenyl, 4-, 5-, 6- or 7-benzo[1,3]dioxolyl,8-quinolinyl, 2-indolyl, 3-indolyl and pyridinyl. Most preferably Ar,optionally substituted as described above, is phenyl or naphthyl.Specific Ar are selected from the group consisting of phenyl,2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2,5-dimethyl-phenyl,2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 2-fluoro-3-trifluoromethyl-phenyl,2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2,3-difluoro-phenyl,2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichloro-phenyl,3,4-dichlorophenyl, 2,6-dichlorophenyl, 3-iodo-phenyl,2-chloro-4-fluoro-phenyl, benzofuran-3-yl, 2-methoxy-phenyl,3-methoxy-phenyl, 4-methoxy-phenyl, 2,3-dimethoxy-phenyl,3-trifluoromethoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-ethoxy-phenyl,3-trifluoromethylsulfanyl-phenyl, naphthalen-1-yl, naphthalen-2-yl,benzo[b]thiophen-4-yl, 3-nitro-phenyl, benzo[1,3]dioxol-5-yl,pyridin-3-yl, pyridin-4-yl, 3-indolyl, 1-methyl-indol-3-yl, 4-biphenyl,3,5-dimethyl-phenyl, 3-isopropoxy-phenyl, 3-dimethylamino-phenyl,2-fluoro-5-methyl-phenyl, and 2-methyl-3-trifluoromethyl-phenyl.Preferably, there are 0, 1 or 2 R^(r) substituents.

Preferably R^(r) is selected from the group consisting of —OH, —CH₃,—CH₂CH₃, -propyl, -t-butyl, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, phenyl,—Ophenyl, benzyl, —Obenzyl, cyclopentyl, cyclohexyl, —Ocyclopentyl,—Ocyclohexyl, —CN, —NO₂, —NH₂, —N(CH₃)₂, —N(CH₂CH₃)₂,pyrrolidin-2-on-1-yl, piperidin-1-yl, 2- or 3-pyrrolin-1-yl,morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, pyrrolidin-1-yl,—C(O)NH₂, —C(O)N(CH₃)₂, —C(O)NH(CH₃), —NHCOCH₃, —NHSO₂CH₃, —C(O)CH₃,—SOCH₃, —SO₂CH₃, —SO₂N(CH₃)₂, —SCF₃, —F, —Cl, —Br, —I, —CF₃, —OCF₃, and—COOCH₃.

Most preferably R^(r) is selected from the group consisting of —CH₃,—OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —F, —Cl, —Br, —CF₃, and —OCF₃.

Preferably R⁴ is selected from the group consisting of:

-   -   I) —COOH, —COOCH₃, —COOCH₂CH₃,    -   II)—CONH(CH₃), —CONH(CH₂CH₃), —CONH(CH₂CH₂CH₃), —CONH(CH(CH₃)₂),        —CONH(CH₂CH₂CH₂CH₃), —CONH(CH(CH₃)CH₂CH₃), —CONH(C(CH₃)₃),        —CONH(cyclohexyl), —CONH(2-hydroxy-cyclohexyl), —CON(CH₃)₂,        —CONCH₃(CH₂CH₃), —CONCH₃(CH₂CH₂CH₃), —CONCH₃(CH(CH₃)₂),        —CONCH₃(CH₂CH₂CH₂CH₃), —CONCH₃(CH(CH₃)CH₂CH₃), —CONCH₃(C(CH₃)₃),        —CON(CH₂CH₃)₂, —CO-piperidin-1-yl, —CO-morpholin-4-yl,        —CO-piperazin-1-yl, —CO-pyrrolidin-1-yl, —CO-2-pyrrolin-1-yl,        —CO-3-pyrrolin-1-yl, and —CO-piperidin-1-yl.

Most preferably R⁴ is —COOH.

Preferred compounds have demonstrated CCK-1 agonist or antagonistactivity, and are selected from the group consisting of:

EX Compound

-   1    (Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylic    acid;-   2    (E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylic    acid;-   3    (Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylic    acid;-   4    (Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-acrylic    acid;-   5    (Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(4-chloro-phenyl)-acrylic    acid;-   6    (Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylic    acid;-   7    (Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylic    acid;-   8    (Z)-2-(3-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-acrylic    acid;-   9    (Z)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylic    acid;-   10    (Z)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylic    acid;-   11    (Z)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylic    acid;-   12    (Z)-2-(3-Chloro-phenyl)-3-(5-naphthalen-2-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-acrylic    acid;-   13    (E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-acrylic    acid;-   14    (E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylic    acid;-   15    (E)-2-(4-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-acrylic    acid;-   16    (E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylic    acid;-   17    (E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylic    acid;-   18    (E)-2-(3-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-acrylic    acid;-   19    (E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylic    acid;-   20    (E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(4-chloro-phenyl)-acrylic    acid;-   21    (E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylic    acid;-   22    (E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylic    acid;-   23    (E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-acrylic    acid;-   24    3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-propionic    acid;-   25    2-(3-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-propionic    acid;-   26    3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionic    acid;-   27    3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-propionic    acid;-   28    2-(4-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-propionic    acid;-   29    3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-propionic    acid;-   30 3-(4,5-Di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acid;-   31 3-(1-Methyl-4,5-di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic    acid;-   32    3-[4,5-Bis-(2-chloro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionic    acid;-   33    3-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionic    acid;-   34    3-[4,5-Bis-(4-fluoro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionic    acid; and-   35    (Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylic    acid, sodium salt.

Pharmaceutically acceptable salts, esters, and amides includecarboxylate salts (e.g., C₁₋₈alkyl, C₃₋₈cycloalkyl, aryl,C₂₋₁₀heteroaryl, or C₂₋₁₀ non-aromatic heterocyclic), amino additionsalts, acid addition salts, esters, and amides that are within areasonable benefit/risk ratio, pharmacologically effective and suitablefor contact with the tissues of patients without undue toxicity,irritation, or allergic response. Representative salts for compounds offormula (I) displaying basic functionality include hydrobromide,hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate,oleate, palmitate, stearate, laurate, borate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,naphthylate, mesylate, glucoheptonate, lactiobionate, andlaurylsulfonate. Representative addition salts for compounds of formula(I) displaying acidic functionality are those that form non-toxic basesalts with such compounds. These salts may include alkali metal andalkali earth cations such as sodium, potassium, calcium, and magnesium,as well as non-toxic ammonium, quaternary ammonium, and amine cationssuch as tetramethyl ammonium, methylammonium, trimethylammonium, andethylammonium. See example, S. M. Berge, et al., “Pharmaceutical Salts,”J. Pharm. Sci., 1977, 66:1-19, which is incorporated herein byreference. Examples of suitable salts include(Z)-3-[5-benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylicacid, sodium salt.

Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di(C₁₋₆alkyl) amines. Secondary amines include 5- or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃alkylprimary amines, and di(C₁₋₂alkyl)amines. Representative pharmaceuticallyacceptable esters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl,phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred esters include methylesters.

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. Publications describedherein are incorporated by reference in their entirety.

The compounds as described above may be made according to processeswithin the skill of the art and/or that are described in the schemes andexamples that follow. To obtain the various compounds herein, startingmaterials may be employed that carry the ultimately desired substituentsthough the reaction scheme with or without protection as appropriate.Alternatively, it may be necessary to employ, in the place of theultimately desired substituent, a suitable group that may be carriedthrough the reaction scheme and replaced as appropriate with the desiredsubstituent.

The compounds as described above may be made according to Schemes A-Fbelow. Persons skilled in the art will recognize that certain compoundsare more advantageously produced by one scheme as compared to the other.

Referring to Scheme A, there are disclosed the following notes andadditions. The Grignard reagent A1 can be purchased or synthesized fromthe corresponding arylmethyl bromide. Certain substituents on R¹ thatare incompatible with the reaction conditions required to form A1 mayrequire protection. Oxidation of alcohol A3 can be accomplished using avariety of conditions including Dess-Martin oxidation or Swern oxidationconditions. Diketone A5 can optionally be obtained by the methoddescribed in Scheme B or the diketone can be obtained from commercialsources. The synthesis of imidazole A6 using HMTA(hexamethylene-tetramine) can also be accomplished with formaldehyde andNH₄OAc. The protection (SEM) of imidazole A6 can also be accomplishedwith alternate protecting groups such as MEM, MOM, or benzyl. Arylaceticacids used to make A8 can be obtained from commercial sources or made bymethods described by Z. Wang et al. (Synth. Commun. 1999, 29:2361-2364),or T. Saito et al. (J. Am. Chem. Soc. 1998, 120:11633-11644). Thecondensation of A7 with arylacetic acids results in a mixture of olefinisomers A8 (E) and A8 (Z). These isomers can typically be separated andisolated using chromatographic methods. Additionally, pure isomers A8(E) and A8 (Z) can be isomerized to mixtures using photolysis andfurther separated by chromatographic methods. Reduction of A8 to A9 canbe accomplished using TsNHNH₂ to produce a racemic mixture of acid A9.This mixture of optical isomers can be separated by chiralchromatographic methods. Alternatively, the reduction can beaccomplished using catalytic hydrogenation methods or transferhydrogenation methods.

Referring to Scheme B, there are disclosed the following notes andadditions. Scheme B shows an alternative to the synthesis of diketoneA5, which is then used in Scheme A to synthesize the desired products.Alkyne B1 can be obtained from commercial sources or synthesized bystandard synthetic methods, such as coupling of trimethylsilylacetylenewith an aryl bromide or iodide using a Sonogashira reaction, or byhomologation of an aryl aldehyde using (EtO)₂P(O)C(N₂)C(O)CH₃.

Referring to Scheme C, there are disclosed the following notes andadditions. The starting acid can come from A9, F2, or when appropriatethe imidazole can be protected at the R³ position with a protectinggroup such as SEM. Of course, analogous acid A8 can be used to produceanalogous C4 or C5. The reduction to C1 may be effected with a number ofreducing agents including DIBAL-H and LAH. The oxidation reactionproducing C2 may be carried out using Swern or Dess-Martin conditions.One carbon homologation to C3 is accomplished by a Wittig reaction using(methoxymethyl)triphenyl-phosphonium bromide and base, followed byoxidation to the acid C4. Alternatively the two carbon homologated acidsC5 can be obtained by Horner-Emmons reaction, using (EtO)₂P(O)CH₂CO₂Etto provide the acrylate, followed by reduction of the double bond byhydrogenation, and hydrolysis of the ester using a base such as LiOH.

Referring to Scheme D, there are disclosed the following notes andadditions. Ester D1 can be obtained from commercial sources orsynthesized using methods described by Z. Wang et al. (Synth. Commun.1999, 29:2361-2364) or T. Saito et al. (J. Am. Chem. Soc. 1998,120:11633-11644). Ester D2 can be prepared through deprotonation andreaction with allyl bromide. The olefin in D2 can be cleaved underozonolysis conditions or with an osmium tetroxide/sodium periodateprotocol to provide aldehyde D3. Condensation of the aldehyde D3 withbenzoin A5 then affords esters of type D4. Hydrolysis with LiOH oranother suitable base then affords the acid A9.

Referring to Scheme E, there are disclosed the following notes andadditions. As shown, any of the acids A9, C4, C5, or F2, can be employedas a starting material. Of course, analogous acid A8 can be used toproduce analogous E1. Alternatively, ester D4 might also be employedwhere Me₃Al is used as a Lewis Acid with NHR⁶R⁷. Amines can be obtainedfrom commercial sources or synthesized by known synthetic methods.Additionally, the amide bond formation can be accomplished by any numberof known peptide coupling methods including DIC/DMAP or DCC. In somecases protection of the imidazole at the R³ position with SEM or someother protecting group may be required.

Referring to Scheme F, there are disclosed the following notes andadditions. The starting ester D4 may be used, or alternatively estersobtained from acids A9, C4, or C5 may also be used to obtain thecorresponding N-alkylated compounds F1. Of course, analogous acid A8 canbe used to produce analogous F1 or F2. Alkyl halides would preferably becommercial or synthesized bromides or iodides, but in some cases alkylchlorides could be used. Hydrolysis of ester F1 can be accomplished asdescribed in Scheme D to provide the desired acid F2.

Compounds of the present invention may be administered in pharmaceuticalcompositions to treat patients (humans and other mammals) with disordersmediated by the CCK-1 receptor. As CCK-1 receptor modulators, thecompounds may be divided into compounds that are pure or partialagonists and compounds that are antagonists or inverse agonists. Wherethe compound is a CCK-1 receptor antagonist or inverse agonist, it maybe used in the treatment of pain, drug dependence, anxiety, panicattack, schizophrenia, pancreatic disorder, secretory disorder,gastrointestinal motility disorders, functional bowel disease, biliarycolic, anorexia and cancer. Where the compound is a CCK-1 receptoragonist, it may be used in the treatment of obesity, hypervigilance andgallstones.

The pharmaceutical compositions can be prepared using conventionalpharmaceutical excipients and compounding techniques known to thoseskilled in the art of preparing dosage forms. It is anticipated that thecompounds of the invention can be administered by oral, parenteral,rectal, topical, or ocular routes or by inhalation. Preparations mayalso be designed to give slow release of the active ingredient. Thepreparation may be in the form of tablets, capsules, sachets, vials,powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, compounds may beadministered by intravenous infusion or topical administration, but morepreferably by oral administration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. Tablets for oral use may include the active ingredient mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservatives agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like; typical liquidoral excipients include ethanol, glycerol, water and the like. Starch,polyvinyl-pyrrolidone, sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, will generally be magnesium stearate, stearic acid or talc. Ifdesired, the tablets may be coated with a material such as glycerylmonostearate or glyceryl distearate to delay absorption in thegastrointestinal tract, or may be coated with an enteric coating.Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid, semi-solid, or liquid diluent, andsoft gelatin capsules wherein the active ingredient is mixed with water,an oil such as peanut oil or olive oil, liquid paraffin, a mixture ofmono and di-glycerides of short chain fatty acids, polyethylene glycol400, or propylene glycol.

Liquids for oral administration may be suspensions, solutions, emulsionsor syrups or may be presented as a dry product for reconstitution withwater or other suitable vehicles before use. Compositions of such liquidmay contain pharmaceutically-acceptable excipients such as suspendingagents (for example, sorbitol, methyl cellulose, sodium alginate,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel and the like); non-aqueous vehicles, which include oils(for example, almond oil or fractionated coconut oil), propylene glycol,ethyl alcohol or water; preservatives (for example, methyl or propylp-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and,if needed, flavoring or coloring agents.

The compounds of this invention may also be administered by non-oralroutes. The compositions may be formulated for rectal administration asa suppository. For parenteral use, including intravenous, intramuscular,intraperitoneal, or subcutaneous routes, the compounds of the inventionwill generally be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity or in parenterallyacceptable oil. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Such forms will be presented in unit dose formsuch as ampules or disposable injection devices, in multi-dose formssuch as vials from which the appropriate dose may be withdrawn, or in asolid form or pre-concentrate that can be used to prepare an injectableformulation. Another mode of administration of the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery. The compounds of this invention may also be administered byinhalation, via the nasal or oral routes using a spray formulationconsisting of the compound of the invention and a suitable carrier.

Effective doses of the compounds of the present invention may beascertained by conventional methods. The specific dosage level requiredfor any particular patient will depend on a number of factors, includingseverity of the condition being treated, the route of administration,and the weight of the patient. Oral doses range from about 0.05 to 200mg/kg, daily, taken in 1 to 4 separate doses. Some compounds of theinvention may be orally dosed in the range of about 0.05 to about 50mg/kg daily, others may be dosed at 0.05 to about 20 mg/kg daily, whilestill others may be dosed at 0.1 to about 10 mg/kg daily. Infusion dosescan range from about 1 to 1000 μg/kg/min of inhibitor, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days. For topical administration compounds of the presentinvention may be mixed with a pharmaceutical carrier at a concentrationof about 0.1% to about 10% of drug to vehicle.

EXAMPLES

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz) orDPX500 (500 MHz) spectrometer. The format of the ¹H NMR data below is:chemical shift in ppm down field of the tetramethylsilane reference(multiplicity, coupling constant J in Hz, integration).

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative mode asindicated. The “mass calculated” for a molecular formula is themonoisotopic mass of the compound.

Protocols for Reversed-Phase HPLC

Reversed-Phase HPLC was performed on a Hewlett Packard (Agilent) 1100 atroom temperature using the methods described below. Retention times arereported in minutes.

Method A

-   Column: Xterra™, RP18, 3.5 μm, 4.6×50 mm-   Mobile Phase Acetonitrile/Water with 0.1% TFA-   Flow rate: 1.5 mL/min-   Detection wavelength: 220 & 254 nm-   Gradient (Acetonitrile/Water):

1) 0.0 min 1.0% Acetonitrile  2) 3.5 min 85% Acetonitrile 3)   5 min 85%AcetonitrileMethod B

-   Column: XTerra Prep MS C18, 5 μm, 19×50 mm-   Mobile Phase Acetonitrile/Water with 0.1% TFA-   Flow rate: 25 mL/min-   Detection wavelength: 220 & 254 nm-   Gradient:

1)  0.0 min 15% Acetonitrile 2) 13.0 min 99% Acetonitrile 3) 15.0 min99% AcetonitrileMethod C

-   Column: Zorbax Eclipse XDB-C8, 5 μm, 4.6×150 mm-   Mobile Phase Acetonitrile/Water with 0.1% TFA-   Flow rate: 0.75 mL/min-   Detection wavelength: 220 & 254 nm-   Gradient (Acetonitrile/Water):

1) 0.0 min  1% Acetonitrile 2) 8.0 min 99% Acetonitrile 3) 12.0 min  99%AcetonitrileMethod D

-   Column: Chromolith SpeedROD, RP18e, 4.6×50 mm-   Mobile Phase Acetonitrile/Water with 0.1% TFA-   Flow rate: 5.0 mL/min-   Detection wavelength: 220 & 254 nm-   Gradient (Acetonitrile/Water):

1) 0.0 min 1.0% Acetonitrile  2) 2.0 min 85% Acetonitrile 3) 3.0 min 85%Acetonitrile

Normal-phase Column Chromatography

Normal-phase column chromatography was accomplished using ISCO Foxy 200or ISCO OPTIX 10X systems employing one of the following commerciallyavailable prepacked columns: Biotage 40S (SiO₂ 40 g), Biotage 40M (SiO₂90 g), Biotage 40L (SiO₂ 120 g), Biotage 65M (SiO₂ 300 g) or ISCORedisep (SiO₂, 10 g, 12 g, 35 g, 40 g, or 120 g).

Example 1

(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylicacid

The title compound was prepared as described in Scheme A using thefollowing procedure.

A. 1-Benzo[1,3]dioxol-5-yl-2-(2,5-dichloro-phenyl)-ethanol. To a stirred0.5 M solution of (2,5-dichloro-benzyl)-magnesium bromide in THF (500mL, 250 mmol) under N₂ at 0° C. was addedbenzo[1,3]dioxole-5-carbaldehyde (17.0 g, 113.0 mmol) in small portions.The reaction mixture was allowed to warm to room temperature (rt) andwas stirred for 1 h. The mixture was diluted with 1 N HCl (200 mL) andEtOAc (200 mL). The layers were separated, and the organic layer washedwith brine, dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude solid was recrystallized from Et₂O/hexane to give 24.8 g (69%) ofa white solid. HPLC: R_(t)=1.35 (Method D). ¹H NMR (500 MHz, CDCl₃):7.30 (d, J=8.5 Hz, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.16 (dd, J=8.5, 2.7 Hz,1H), 6.91 (d, J=1.4 Hz, 1H), 6.80 (dd, J=8.0, 1.6 Hz, 1H), 6.77 (d,J=8.0 Hz, 1H), 5.97 (q, J=2.5, 1.4 Hz, 2H), 4.93-4.89 (m, 1H), 3.10 (dd,J=13.7, 4.4 Hz, 1H), 3.01 (dd, J=13.7, 8.5 Hz, 1H), 1.88 (d, J=3.0 Hz,1H).

B. 1-Benzo[1,3]dioxol-5-yl-2-(2,5-dichloro-phenyl)-ethanone. To astirred solution of the alcohol from step A (7.08 g, 22.7 mmol) inCH₂Cl₂ (300 mL) under N₂ at 0° C. was added Dess-Martin reagent (12.5 g,29.5 mmol) in portions. The reaction mixture was allowed to warm to rtand was stirred for 2 h. The mixture was then poured into a vigorouslystirred solution of Na₂S₂O₃ (˜51 g) in satd aq Na₂HCO₃ (200 mL), and theresulting mixture was stirred for 1.5 h. The layers were separated, andthe organic layer washed with brine, dried (Na₂SO₄), and concentratedunder reduced pressure. The crude ketone was carried on without furtherpurification (6.40 g, 91%). HPLC: R_(t)=2.94 (Method A). MS (ESI): masscalculated for C₁₅H₁₀Cl₂O₃, 308.00; m/z found, 309.0 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.65 (dd, J=8.2, 1.6 Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.33(d, J=8.5 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 7.21 (dd, J=2.7, 8.5 Hz, 1H),6.89 (d, J=8.2 Hz, 1H), 6.07 (s, 2H), 4.32 (s, 2H), 1.55 (s, 1H).

C. 1-Benzo[1,3]dioxol-5-yl-2-bromo-2-(2,5-dichloro-phenyl)-ethanone. Toa stirred solution of the ketone from step B (5.30 g, 17.1 mmol) inCH₂Cl₂ (40 mL) under N₂ at 0° C. was added a solution of Br₂ (3.07 g,19.2 mmol) in AcOH (100 mL) dropwise over a period of 10 min. Thereaction mixture was stirred overnight, and the solvent was removedunder reduced pressure. The residue was then dissolved in EtOAc (200 mL)and satd aq NaHCO₃ (150 mL) was added slowly. The layers were separated,and the organic layer washed with brine, dried (Na₂SO₄) and concentratedunder reduced pressure. The crude solid residue was carried on withoutfurther purification. HPLC: R_(t)=1.57 (Method D). ¹H NMR (500 MHz,CDCl₃): 7.67 (d, J=2.5 Hz, 1H), 7.60 (dd, J=8.2, 2.0 Hz, 1H), 7.47 (d,J=1.8 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.73 (s,1H), 6.07 (s, 2H), 1.55 (br s, 1H).

D. 1-Benzo[1,3]dioxol-5-yl-2-(2,5-dichloro-phenyl)-ethane-1,2-dione. Thecrude bromide from step C was dissolved in DMSO (35 mL), and thesolution was heated to 65° C. for 6 h. The solution was then cooled tort, and Et₂O (200 mL) and H₂O (100 mL) were added. The layers wereseparated, and the organic layer washed with H₂O then brine, dried(Na₂SO₄), and concentrated under reduced pressure. The resulting solidwas vigorously stirred in Et₂O (100 mL), filtered off, washed with Et₂O(100 mL), and dried under vacuum. The crude, bright yellow solid wascarried on without further purification (4.0 g, 72%). HPLC: R_(t)=1.47(Method D). ¹H NMR (500 MHz, CDCl₃): 7.84 (d, J=2.7 Hz, 1H), 7.61 (dd,J=8.2, 1.9 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.49 (dd, J=8.5, 2.7 Hz,1H), 7.36 (d, J=8.5 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.11 (s, 2H).

E. 5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazole. Asuspension of the diketone from step D (3.70 g, 11.4 mmol),hexamethylenetetramine (HMTA; 4.82 g, 34.4 mmol) and NH₄OAc (5.27 g,68.7 mmol) in AcOH (23 mL) was heated to 95° C. After 30 min, additionalAcOH (17 mL) was added, and the resulting solution was stirred for 2 h.The solution was allowed to cool to rt, and solvent was removed underreduced pressure. The residue was dissolved in EtOAc (200 mL), and satdaq NaHCO₃ (150 mL) was added slowly. The resulting layers wereseparated, and the organic layer washed with brine, dried (Na₂SO₄), andconcentrated under reduced pressure. The resulting crude solid wascarried on without further purification (3.8 g, 100%). HPLC: R_(t)=0.84(Method D). MS (ESI): mass calculated for C₁₆H₁₀Cl₂N₂O₂, 332.01; m/zfound, 333.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.72 (s, 1H), 7.43-7.37(m, 2H), 7.29-7.27 (m, 1H), 6.84 (br s, 2H), 6.76-6.74 (m, 1H), 5.96 (s,2H).

F.5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole.To a stirred solution of the imidazole from step E (3.80 g, 11.3 mmol)in DMF (30 mL) under N₂ at 0° C. was added NaH (60% dispersion inmineral oil; 0.59 g, 14.8 mmol), and the reaction mixture was stirredfor 35 min. 2-(Trimethylsilyl)ethoxymethyl chloride (SEM-Cl; 2.21 mL,12.4 mmol) was added in one portion, and the resulting mixture wasallowed to warm to rt and was stirred for 40 min. The solvent wasremoved under reduced pressure, and EtOAc (100 mL) and H₂O (100 mL) wereadded to the residue. The layers were separated, and the organic layerwashed with brine, dried (Na₂SO₄), and concentrated under reducedpressure. The crude solid residue was purified on silica gel (CH₂Cl₂) toafford an inseparable mixture of regioisomers (3.25 g, 62%). HPLC:R_(t)=1.30 (Method D). MS (ESI): mass calculated for C₂₂H₂₄Cl₂N₂O₃Si,462.09; m/z found, 463.1 [M+H]⁺. ¹H NMR of mixture of two isomers (500MHz, CDCl₃): Isomer 1: 7.77 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.44 (dd,J=8.6, 2.5 Hz, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.00 (d, J=1.3 Hz, 1H), 6.97(dd, J=8.0, 1.5 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 5.96 (s, 2H), 5.18 (d,J=10.9 Hz, 1H), 5.03 (d, J=10.9 Hz, 1H), 3.42 (t, J=8.1 Hz, 2H),0.89-0.85 (m, 2H), 0.00 (s, 9H); Isomer 2: 7.78 (s, 1H), 7.45 (d, J=2.5Hz, 2H), 7.43 (d, J=2.5 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H) 7.31 (d, J=8.6Hz, 1H), 7.22 (dd, J=8.6, 2.5 Hz, 1H), 6.84 (d, J=1.6 Hz, 1H) 6.02 (s,2H), 5.26 (s, 2H), 3.62-3.57 (m, 1H), 0.99-0.95 (m, 2H), 0.05 (s, 9H).

G.5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde.To a stirred solution of the imidazole from step F (3.25 g, 7.01 mmol)in THF (30 mL) under N₂ at −78° C. was added lithium diisopropylamide(2.0 M LDA in THF; 4.21 mL, 8.41 mmol), and the reaction mixture wasstirred for 35 min. To this mixture was added dry DMF (2.71 mL, 35.1mmol) in one portion, and the resulting mixture was allowed to warm tort and was stirred for 2 h. Twenty milliliters of 1 N HCl was added. Thereaction mixture was stirred for 1 h, and then EtOAc (100 mL) and H₂O(100 mL) were added. The layers were separated, and the organic layerwashed with brine, dried (Na₂SO₄), and concentrated under reducedpressure. The crude solid residue was purified on silica gel(EtOAc/hexanes) to afford an inseparable mixture of regioisomers (2.11g, 62%). MS (ESI): mass calculated for C₂₃H₂₄Cl₂N₂O₄Si, 490.09; m/zfound, 491.0 [M+H]⁺. ¹H NMR of mixture of two isomers (400 MHz, CDCl₃):Isomer 1: 9.98 (s, 1H), 7.04 (dd, J=1.8, 0.4 Hz, 2H), 6.98 (dd, J=8.0,1.8 Hz, 2H), 6.78 (d, J=8.0 Hz, 2H), 6.00 (s, 2H), 5.89 (d, J=10.2 Hz,1H), 5.74 (s, 1H), 5.38 (d, J=10.4 Hz, 1H), 3.76-3.72 (m, 1H), 1.03-0.98(m, 2H), 0.00 (s, 9H); Isomer 2: 9.94 (s, 1H), 7.55 (dd, J=8.6, 0.6 Hz,2H), 7.51 (dd, J=8.6, 2.3 Hz, 2H), 7.47 (dd, J=2.3, 0.6 Hz, 2H), 6.06(s, 2H), 5.89 (d, J=10.2 Hz, 1H), 5.74 (s, 1H), 5.38 (d, J=10.4 Hz, 1H),3.57-3.47 (m, 1H), 0.92-0.84 (m, 2H), 0.00 (s, 9H).

H.(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylicacid. To a stirred solution of the aldehyde from Step G (0.10 g, 0.20mmol) and (3-chloro-phenyl)-acetic acid (52 mg, 0.31 mmol) in Ac₂O (0.3mL) was added Et₃N (0.3 mL). The mixture was stirred for 30 min, and thesolution volume was decreased under reduced pressure. The crude mixturewas filtered through silica (0-10% MeOH/CH₂Cl₂), and the filtrate wasconcentrated to afford crude SEM-protected imidazole (119 mg).Trifluoroacetic acid (TFA; 0.5 mL) was added to a solution of theresidue in CH₂Cl₂ (0.5 mL), and the mixture was stirred at rt for ˜6 h.The solvent was removed under reduced pressure, and the residue waspurified by reversed-phase chromatography (Method B) to provide theE-stereoisomer (Example 2) and the title Z-stereoisomer (42 mg, 40%).HPLC: R_(t)=1.39 (Method D). MS (ESI): mass calculated forC₂₅H₁₅Cl₃N₂O₄, 512.01; m/z found, 513.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.36 (t, J=2.0 Hz, 1H), 7.35-7.31 (m, 2H), 7.29-7.25 (m, 2H), 7.22 (td,J=7.6, 1.3 Hz, 1H), 7.11-7.07 (m, 1H), 6.95 (s, 1H), 6.79 (dd, J=8.1,1.8 Hz, 1H), 6.72 (d, J=1.8 Hz, 1H), 6.67 (d, J=8.1 Hz, 1H), 5.90 (s,2H).

Example 2

(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylicacid

The title compound was prepared as described in Example 1 and isolatedby reversed-phase chromatography (Method B) to afford 42 mg (40%) of thedesired acid. HPLC: R_(t)=1.22 (Method D). MS (ESI): mass calculated forC₂₅H₁₅Cl₃N₂O₄, 512.01; m/z found, 513.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):8.06 (s, 1H), 7.47 (t, J=7.4 Hz, 1H), 7.39-7.33 (m, 2H), 7.32-7.20 (m,4H), 6.72 (d, J=8.2 Hz, 1H), 6.57 (br d, J=7.7 Hz, 1H), 6.51 (br s, 1H),5.97 (s, 2H).

Example 3

(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylicacid

The title compound was prepared as in Example 1 and Scheme A,substituting m-tolyl-acetic acid for (3-chloro-phenyl)-acetic acid instep H (5% yield). HPLC: R_(t)=1.28 (Method D). MS (ESI): masscalculated for C₂₆H₁₈Cl₂N₂O₄, 492.06; m/z found, 493.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.47-7.40 (m, 2H), 7.19 (br s, 1H), 7.15 (br d, J=8.0Hz, 1H), 7.01-6.96 (m, 3H), 6.92 (br d, J=7.7 Hz, 1H), 6.84 (d, J=8.0Hz, 1H), 6.70 (dd, J=8.2, 1.9 Hz, 1H), 6.52 (d, J=1.6 Hz, 1H), 6.05 (s,2H), 2.12 (s, 3H).

Example 4

(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-acrylicacid

The title compound was prepared as in Example 1 and Scheme A,substituting naphthalen-1-yl-acetic acid for (3-chloro-phenyl)-aceticacid in step H (3% yield). HPLC: R_(t)=1.40 (Method D). MS (ESI): masscalculated for C₂₉H₁₈Cl₂N₂O₄, 528.06; m/z found, 529.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.78 (br d, J=8.8 Hz, 1H), 7.74 (br d, J=8.0 Hz, 1H),7.64-7.61 (m, 1H), 7.53-7.46 (m, 2H), 7.43-7.39 (m, 3H), 7.09 (s, 1H),6.86 (br s, 1H), 6.80 (br d, J=7.7 Hz, 1H), 6.67 (br d, J=9.0 Hz, 1H),6.49 (s, 1H), 6.05 (s, 2H).

Example 5

(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(4-chloro-phenyl)-acrylicacid

The title compound was prepared as in Example 1 and Scheme A,substituting (4-chloro-phenyl)-acetic acid for (3-chloro-phenyl)-aceticacid in step H (6% yield). HPLC: R_(t)=1.39 (Method D). MS (ESI): masscalculated for C₂₅H₁₅Cl₃N₂O₄, 512.01; m/z found, 513.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.45-7.41 (m, 2H), 7.29 (br d, J=8.5 Hz, 2H), 7.20 (s,1H), 7.08 (br d, J=8.5 Hz, 2H), 6.98 (s, 1H), 6.83 (br d, J=8.2 Hz, 1H),6.78-6.75 (m, 1H), 6.62 (br s, 1H), 6.03 (s, 2H).

Example 6

(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylicacid

The title compound was prepared as in Example 1 and Scheme A,substituting p-tolyl-acetic acid for (3-chloro-phenyl)-acetic acid instep H (6% yield). HPLC: R_(t)=1.26 (Method D). MS (ESI): masscalculated for C₂₆H₁₈Cl₂N₂O₄, 492.06; m/z found, 493.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.44 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.5, 2.2 Hz, 1H),7.27-7.23 (m, 2H), 7.17 (br d, J=1.9 Hz, 1H), 6.97-6.92 (m, 3H),6.83-6.77 (m, 2H), 6.64 (s, 1H), 6.01 (s, 2H), 2.18 (s, 3H).

Example 7

(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylicacid

The title compound was prepared as in Example 1 and Scheme A,substituting (3-trifluoromethyl-phenyl)-acetic acid for(3-chloro-phenyl)-acetic acid in step H (6% yield). HPLC: R_(t)=1.44(Method D). MS (ESI): mass calculated for C₂₆H₁₅Cl₂F₃N₂O₄, 546.04; m/zfound, 547.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.67 (s, 1H), 7.57 (br d,J=9.0 Hz, 1H), 7.47-7.36 (m, 3H), 7.27-7.22 (m, 1H), 7.13-7.07 (m, 2H),6.81 (d, J=8.0 Hz, 1H), 6.71 (dd, J=8.2, 1.9 Hz, 1H), 6.59 (d, J=1.6 Hz,1H), 6.03 (s, 2H).

Example 8

(Z)-2-(3-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-acrylicacid

The title compound was prepared as in Example 1 and Scheme A,substituting (3,4-dichloro-benzyl)-magnesium bromide for(2,5-dichloro-benzyl)-magnesium bromide, and 4-methoxy-benzaldehyde forbenzo[1,3]dioxole-5-carbaldehyde in step A (4% overall yield). HPLC:R_(t)=1.51 (Method D). MS (ESI): mass calculated for C₂₅H₁₇Cl₃N₂O₃,498.03; m/z found, 499.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.48-7.44 (m,2H), 7.37 (br s, 1H), 7.30-7.20 (m, 3H), 7.06-6.99 (m, 3H), 6.94 (d,J=8.5 Hz, 2H), 3.86 (s, 3H).

Example 9

(Z)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylicacid

The title compound was prepared as in Example 1 and Scheme A,substituting (3,4-dichloro-benzyl)-magnesium bromide for(2,5-dichloro-benzyl)-magnesium bromide, and 4-methoxy-benzaldehyde forbenzo[1,3]dioxole-5-carbaldehyde in step A, and substitutingm-tolyl-acetic acid for (3-chloro-phenyl)-acetic acid in step H (3%overall yield). HPLC: R_(t)=1.38 (Method D). MS (ESI): mass calculatedfor C₂₆H₂₀Cl₂N₂O₃, 478.09; m/z found, 479.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.46 (br d, J=8.3 Hz, 1H), 7.37 (br s, 1H), 7.27-7.23 (m, 2H),7.21-7.16 (m, 2H), 7.12 (br d, J=6.8 Hz, 1H), 6.98-6.88 (m, 5H), 3.87(s, 3H), 2.08 (s, 3H).

Example 10

(Z)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylicacid

The title compound was prepared as in Example 1 and Scheme A,substituting (3,4-dichloro-benzyl)-magnesium bromide for(2,5-dichloro-benzyl)-magnesium bromide, and 4-methoxy-benzaldehyde forbenzo[1,3]dioxole-5-carbaldehyde in step A, and substituting(3-trifluoromethyl-phenyl)-acetic acid for (3-chloro-phenyl)-acetic acidin step H (7% overall yield). HPLC: R_(t)=1.58 (Method D). MS (ESI):mass calculated for C₂₆H₁₇Cl₂F₃N₂O₃, 532.06; m/z found, 533.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 7.67 (br s, 1H), 7.55 (br d, J=8.1 Hz, 1H), 7.45(d, J=2.0 Hz, 1H), 7.39 (br d, J=7.6 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H),7.26-7.20 (m, 3H), 7.18 (dd, J=8.3, 2.0 Hz, 1H), 7.09 (s, 1H), 6.85 (d,J=8.8 Hz, 2H), 3.79 (s, 3H).

Example 11

(Z)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylicacid

The title compound was prepared as in Example 1 and Scheme A,substituting (3,4-dichloro-benzyl)-magnesium bromide for(2,5-dichloro-benzyl)-magnesium bromide, and 4-methoxy-benzaldehyde forbenzo[1,3]dioxole-5-carbaldehyde in step A, and substitutingp-tolyl-acetic acid for (3-chloro-phenyl)-acetic acid in step H (7%overall yield). HPLC: R_(t)=1.28 (Method D). MS (ESI): mass calculatedfor C₂₆H₂₀Cl₂N₂O₃, 478.09; m/z found, 479.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.90 (s, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H),7.28-7.24 (m, 2H), 7.21 (d, J=8.0 Hz, 2H), 7.12 (dd, J=8.3, 2.0 Hz, 1H),7.10 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 3.81 (s, 3H), 2.40 (s,3H).

Example 12

(Z)-2-(3-Chloro-phenyl)-3-(5-naphthalen-2-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-acrylicacid

The title compound was prepared as described in Schemes A and B,starting with the coupling of 2-ethynyl-naphthalene and 2-iodo-pyridine(Scheme B) to prepare the diketone intermediate A5 of Scheme A.

Example 13

(E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-acrylicacid

The title compound was prepared as in Examples 1 and 2 and Scheme A,substituting (3,4-dichloro-benzyl)-magnesium bromide for(2,5-dichloro-benzyl)-magnesium bromide, and 4-methoxy-benzaldehyde forbenzo[1,3]dioxole-5-carbaldehyde in step A of Example 1, andsubstituting naphthalen-1-yl-acetic acid for (3-chloro-phenyl)-aceticacid in step H of Example 1 (7% overall yield). HPLC: R_(t)=1.46 (MethodD). MS (ESI): mass calculated for C₂₉H₂₀Cl₂N₂O₃, 514.09; m/z found,515.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.34 (s, 1H), 8.07 (d, J=8.0 Hz,1H), 8.00 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.68-7.51 (m, 4H),7.31 (d, J=8.3 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.06 (dd, J=8.6, 2.0 Hz,1H), 6.76 (d, J=2.0 Hz, 4H), 3.78 (s, 3H).

Example 14

(E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylicacid

The title compound was prepared as in Examples 1 and 2 and Scheme A,substituting (3,4-dichloro-benzyl)-magnesium bromide for(2,5-dichloro-benzyl)-magnesium bromide, and 4-methoxy-benzaldehyde forbenzo[1,3]dioxole-5-carbaldehyde in step A of Example 1, andsubstituting p-tolyl-acetic acid for (3-chloro-phenyl)-acetic acid instep H of Example 1 (10% overall yield). HPLC: R_(t)=1.28 (Method D). MS(ESI): mass calculated for C₂₆H₂₀Cl₂N₂O₃, 478.09; m/z found, 479.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.90 (s, 1H), 7.37 (d, J=8.4 Hz, 1H),7.29 (d, J=2.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H),7.12 (dd, J=8.4, 2.0 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz,2H), 3.81 (s, 3H), 2.40 (s, 3H).

Example 15

(E)-2-(4-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-acrylicacid

The title compound was prepared as in Examples 1 and 2 and Scheme A,substituting (3,4-dichloro-benzyl)-magnesium bromide for(2,5-dichloro-benzyl)-magnesium bromide, and 4-methoxy-benzaldehyde forbenzo[1,3]dioxole-5-carbaldehyde in step A of Example 1, andsubstituting (4-chloro-phenyl)-acetic acid for (3-chloro-phenyl)-aceticacid in step H of Example 1 (11% overall yield). HPLC: R_(t)=1.35(Method D). MS (ESI): mass calculated for C₂₅H₁₇Cl₃N₂O₃, 498.0; m/zfound, 499.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.94 (s, 1H), 7.40 (d,J=8.6 Hz, 2H), 7.37 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.28-7.24(m, 2H), 7.13 (dd, J=8.3, 2.0 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 6.85 (d,J=8.8 Hz, 2H), 3.82 (s, 3H).

Example 16

(E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylicacid

The title compound was prepared as in Examples 1 and 2 and Scheme A,substituting (3,4-dichloro-benzyl)-magnesium bromide for(2,5-dichloro-benzyl)-magnesium bromide, and 4-methoxy-benzaldehyde forbenzo[1,3]dioxole-5-carbaldehyde in step A of Example 1, andsubstituting (3-trifluoromethyl-phenyl)-acetic acid for(3-chloro-phenyl)-acetic acid in step H of Example 1 (10% overallyield). HPLC: R_(t)=1.46 (Method D). MS (ESI): mass calculated forC₂₆H₁₇Cl₂F₃N₂O₃, 532.06; m/z found, 533.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.99 (s, 1H), 7.63 (br d, J=7.8 Hz, 1H), 7.50-7.40 (m, 3H),7.23-7.25 (m, 2H), 7.07-7.00 (m, 3H), 6.78 (d, J=8.8 Hz, 2H), 3.78 (s,3H).

Example 17

(E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylicacid

The title compound was prepared as in Examples 1 and 2 and Scheme A,substituting (3,4-dichloro-benzyl)-magnesium bromide for(2,5-dichloro-benzyl)-magnesium bromide, and 4-methoxy-benzaldehyde forbenzo[1,3]dioxole-5-carbaldehyde in step A of Example 1, andsubstituting m-tolyl-acetic acid for (3-chloro-phenyl)-acetic acid instep H of Example 1 (3% yield). HPLC: R_(t)=1.30 (Method D). MS (ESI):mass calculated for C₂₆H₂₀Cl₂N₂O₃, 478.09; m/z found, 479.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 8.03 (s, 1H), 7.49-7.43 (m, 1H), 7.40-7.35 (m,3H), 7.23-7.15 (m, 3H), 7.06 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H),3.82 (s, 3H), 2.41 (s, 2H).

Example 18

(E)-2-(3-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-acrylicacid

The title compound was prepared as in Examples 1 and 2 and Scheme A,substituting (3,4-dichloro-benzyl)-magnesium bromide for(2,5-dichloro-benzyl)-magnesium bromide, and 4-methoxy-benzaldehyde forbenzo[1,3]dioxole-5-carbaldehyde in step A of Example 1 (4% overallyield). HPLC: R_(t)=1.43 (Method D). MS (ESI): mass calculated forC₂₅H₁₇Cl₃N₂O₃, 498.03; m/z found, 499.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.10 (s, 1H), 7.44 (brd, J=7.8 Hz, 1H), 7.40-7.33 (m, 4H), 7.23 (br d,J=7.6 Hz, 1H), 7.15 (dd, J=8.3, 2.0 Hz, 1H), 7.10 (d, J=8.8 Hz, 2H),6.85 (d, J=8.8 Hz, 2H), 3.81 (s, 3H).

Example 19

(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylicacid

The title compound was prepared as in Examples 1 and 2 and Scheme A,substituting m-tolyl-acetic acid for (3-chloro-phenyl)-acetic acid instep H of Example 1 (6% overall yield). HPLC: R_(t)=1.16 (Method D). MS(ESI): mass calculated for C₂₆H₁₈Cl₂N₂O₄, 492.06; m/z found, 493.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.06 (s, 1H), 7.49-7.44 (m, 1H),7.38-7.20 (m, 5H), 6.72 (d, J=8.2 Hz, 1H), 6.57 (br d, J=8.0 Hz, 1H),6.51 (br s, 1H), 5.97 (s, 3H), 2.42 (s, 3H).

Example 20

(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(4-chloro-phenyl)-acrylicacid

The title compound was prepared as in Examples 1 and 2 and Scheme A,substituting (4-chloro-phenyl)-acetic acid for (3-chloro-phenyl)-aceticacid in step H of Example 1 (10% overall yield). HPLC: R_(t)=1.21(Method D). MS (ESI): mass calculated for C₂₅H₁₅Cl₃N₂O₄, 512.01; m/zfound, 513.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.00 (s, 1H), 7.40 (d,J=8.5 Hz, 2H), 7.37 (d, J=8.5 Hz, 1H), 7.32 (dd, J=8.5, 2.2 Hz, 1H),7.29-7.25 (m, 2H), 7.22 (d, J=2.5 Hz, 1H), 6.74 (d, J=8.2 Hz, 1H), 6.66(dd, J=8.0, 1.6 Hz, 1H), 6.58 (d, J=2.0 Hz, 1H), 5.97 (s, 2H).

Example 21

(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylicacid

The title compound was prepared as in Examples 1 and 2 and Scheme A,substituting (3-trifluoromethyl-phenyl)-acetic acid for(3-chloro-phenyl)-acetic acid in step H of Example 1 (11% overallyield). HPLC: R_(t)=1.30 (Method D). MS (ESI): mass calculated forC₂₆H₁₅Cl₂F₃N₂O₄, 546.04; m/z found, 547.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 8.09 (s, 1H), 7.71 (br d, J=5.3 Hz, 1H), 7.60 (s, 1H), 7.56 (d,J=5.2 Hz, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 2.2 Hz, 1H),7.22 (d, J=2.2 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 6.64 (dd, J=8.0, 1.6 Hz,1H), 6.57 (d, J=1.6 Hz, 1H), 5.95 (s, 2H).

Example 22

(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylicacid

The title compound was prepared as in Examples 1 and 2 and Scheme A,substituting p-tolyl-acetic acid for (3-chloro-phenyl)-acetic acid instep H of Example 1 (10% overall yield). HPLC: R_(t)=1.16 (Method D). MS(ESI): mass calculated for C₂₆H₁₈Cl₂N₂O₄, 492.06; m/z found, 493.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.02 (s, 1H), 7.38-7.34 (m, 3H), 7.31(dd, J=8.5, 2.2 Hz, 1H), 7.30-7.23 (m, 3H), 6.72 (d, J=8.0 Hz, 1H), 6.58(dd, J=8.2, 1.9 Hz, 1H), 6.49 (d, J=1.6 Hz, 1H), 5.97 (s, 2H), 2.44 (s,3H).

Example 23

(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-acrylicacid

The title compound was prepared as in Examples 1 and 2 and Scheme A,substituting naphthalen-1-yl-acetic acid for (3-chloro-phenyl)-aceticacid in step H of Example 1 (16% yield). HPLC: R_(t)=1.27 (Method D). MS(ESI): mass calculated for C₂₉H₁₈Cl₂N₂O₄, 528.06; m/z found, 529.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.34 (s, 1H), 8.05 (d, J=8.2 Hz, 1H),7.98 (d, J=8.2 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.66-7.62 (m, 1H),7.61-7.52 (m, 3H), 7.25-7.21 (m, 2H), 7.09 (d, J=2.2 Hz, 1H), 6.65 (d,J=8.0 Hz, 1H), 6.39 (br d, J=8.0 Hz, 1H), 6.35 (br s, 1H), 5.93 (s, 2H).

Example 24

3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-propionicacid

A stirred solution of(E)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylicacid (Example 17; 50 mg, 0.084 mmol), p-toluenesulfonylhydrazide (0.24g, 1.26 mmol) and NaOAc (0.10 g, 1.26 mmol) in EtOH (1.0 mL) was heatedto 85° C. for 16 h. The reaction mixture was cooled and then purifieddirectly by reversed-chromatography (Method B) to afford the titlecompound (10 mg, 20%). HPLC: R_(t)=1.19 (Method D). MS (ESI): masscalculated for C₂₆H₂₂Cl₂N₂O₃, 480.10; m/z found, 481.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.54 (d, J=2.0 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H),7.34-7.29 (m, 2H), 7.27 (dd, J=8.3, 2.0 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H),7.17-7.10 (m, 3H), 6.96-6.91 (m, 2H), 4.40 (dd, J=10.1, 5.8 Hz, 1H),3.86 (s, 3H), 3.61 (dd, J=14.9, 10.1 Hz, 1H), 3.29 (dd, J=14.9, 5.8 Hz,1H), 2.34 (s, 3H).

Example 25

2-(3-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-propionicacid

The title compound was prepared using the methods described in Example24 and Scheme A substituting the olefin of Example 18 for the olefin ofExample 17 (22% yield). HPLC: R_(t)=1.19 (Method D). MS (ESI): masscalculated for C₂₅H₁₉Cl₃N₂O₃, 500.05; m/z found, 500.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.55 (d, J=2.0 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H),7.37-7.35 (m, 1H), 7.31-7.28 (m, 5H), 7.27 (dd, J=8.3, 2.3 Hz, 1H),6.96-6.92 (m, 1H), 4.41 (dd, J=9.8, 6.0 Hz, 2H), 3.85 (s, 3H), 3.61 (dd,J=14.9, 9.8 Hz, 1H), 3.30 (dd, J=14.9, 6.1 Hz, 1H).

Example 26

3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionicacid

The title compound was prepared using the methods described in Example24 and Scheme A substituting the olefin of Example 13 for the olefin ofExample 17 (17% yield). HPLC: R_(t)=1.21 (Method D). MS (ESI): masscalculated for C₂₉H₂₂Cl₂N₂O₃, 516.10; m/z found, 517.6 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.22 (d, J=8.5 Hz, 1H), 7.87 (dd, J=8.1, 1.3 Hz, 1H),7.82 (d, J=8.1 Hz, 1H), 7.57-7.46 (m, 4H), 7.45-7.44 (m, 1H), 7.39 (d,J=8.3 Hz, 1H), 7.25-7.21 (m, 2H), 7.18 (dd, J=8.6, 2.3 Hz, 1H),6.93-6.89 (m, 2H), 5.23 (dd, J=9.6, 6.3 Hz, 1H), 3.85 (s, 3H), 3.74 (dd,J=15.2, 9.6 Hz, 1H), 3.40 (dd, J=14.7, 6.3 Hz, 1H).

Example 27

3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-propionicacid

The title compound was prepared using the methods described in Example24 and Scheme A substituting the olefin of Example 16 for the olefin ofExample 17 (22% yield). HPLC: R_(t)=1.18 (Method D). MS (ESI): masscalculated for C₂₆H₁₉Cl₂F₃N₂O₃, 534.07; m/z found, 535.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.62-7.55 (m, 3H), 7.54 (d, J=2.0 Hz, 1H), 7.52-7.46(m, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.32-7.28 (m, 2H), 7.25 (dd, J=8.3, 2.2Hz, 1H), 6.95-6.91 (m, 2H), 4.51 (dd, J=9.8, 5.8 Hz, 1H), 3.85 (s, 3H),3.65 (dd, J=14.9, 9.8 Hz, 1H), 3.32 (dd, J=14.9, 5.8 Hz, 1H).

Example 28

2-(4-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-propionicacid

The title compound was prepared using the methods described in Example24 and Scheme A substituting the olefin of Example 15 for the olefin ofExample 17 (16% yield). HPLC: R_(t)=1.21 (Method D). MS (ESI): masscalculated for C₂₅H₁₉Cl₃N₂O₃, 500.05; m/z found, 501.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.54 (d, J=2.2 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.32(s, 5H), 7.31-7.29 (m, 1H), 7.26 (dd, J=8.5, 2.2 Hz, 1H), 6.94 (t,J=3.0, 1H), 6.93 (t, J=3.0, 1H), 4.41 (dd, J=9.6, 6.3 Hz, 1H), 3.85 (s,3H), 3.63 (dd, J=15.0, 9.6 Hz, 1H), 3.33 (dd, J=14.8, 6.3 Hz, 1H).

Example 29

3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-propionicacid

The title compound was prepared using the methods described in Example24 and Scheme A substituting the olefin of Example 14 for the olefin ofExample 17 (29% yield). HPLC: R_(t)=1.19 (Method D). MS (ESI): masscalculated for C₂₆H₂₂Cl₂N₂O₃, 480.10; m/z found, 481.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.54 (d, J=2.2 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H),7.33-7.29 (m, 2H), 7.27 (dd, J=8.6, 2.2 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H),7.16 (d, J=7.8 Hz, 2H), 6.95-6.91 (m, 2H), 4.39 (dd, J=10.1, 5.8 Hz,1H), 3.85 (s, 3H), 3.59 (dd, J=15.2, 10.1 Hz, 1H), 3.26 (dd, J=15.2, 5.8Hz, 1H), 2.33 (s, 3H).

Example 30

3-(4,5-Di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acid

A. 2-m-Tolyl-pent-4-enoic acid ethyl ester. To a stirred solution ofm-tolyl-acetic acid ethyl ester (10.0 g, 56.1 mmol) in DMF (50 mL) at 0°C. under N₂ was added NaH (60% dispersion in mineral oil; 2.27 g, 61.7mmol). The reaction mixture was allowed to warm to rt and was stirredfor 1.5 h. The mixture was then cooled to 0° C. and was slowly added bycannula to a solution of allyl bromide (20.4 g, 168.3 mmol) in DMF (20mL) at −40° C. over a period of 15 min. The resulting mixture wasstirred 30 min at −40° C. and was then allowed to warm to rt and stirredfor 1 h. The DMF was removed under reduced pressure, and CH₂Cl₂ (100 mL)and H₂O (100 mL) were added to the residue. The resulting layers wereseparated, and the organic layer was washed with brine, dried (Na₂SO₄),and concentrated under reduced pressure.

The crude solid residue was purified on silica gel (EtOAc/hexanes) toafford the desired olefin (9.91 g, 81%). HPLC: R_(t)=10.66 (Method C).¹H NMR (400 MHz, CDCl₃): 7.25-7.18 (m, 1H), 7.12-7.06 (m, 3H), 5.78-5.68(m, 1H), 5.10-4.98 (m, 2H), 4.19-4.04 (m, 2H), 3.61-3.56 (m, 1H),2.85-2.77 (m, 1H), 2.52-2.45 (m, 1H), 2.34 (s, 3H), 1.21 (t, J=7.0 Hz,3H).

B. 4-Oxo-2-m-tolyl-butyric acid ethyl ester. A stirred solution of theolefin from Step A (1.0 g, 4.58 mmol) in 1:1 MeOH/CH₂Cl₂ (25 mL) wascooled to −45° C. A stream of O₃ (Welsbach Ozone Generator T-816-L) wasbubbled through the solution until a light blue color persisted (˜30min). To this solution was added dimethylsulfide (DMS; 2.85 g, 45.8mmol), and the reaction mixture was allowed to warm to rt and wasstirred for 2 h. The solvent was removed under reduced pressure, and theresidue was purified on silica gel (20% EtOAc/hexanes) to afford thedesired aldehyde (0.74 g, 69%). HPLC: R_(t)=2.63 (Method A). ¹H NMR (400MHz, CDCl₃): 9.80 (s, 1H), 7.28-7.22 (m, 1H), 7.12-7.08 (m, 3H),4.25-4.07 (m, 3H), 3.43-3.31 (m, 1H), 2.80 (dd, J=18.6, 4.7 Hz, 1H),2.36 (s, 3H), 1.23 (t, J=7.0 Hz, 3H).

C. 3-(4,5-Di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acid ethylester. The aldehyde of step B (1.91 g, 8.11 mmol) was slowly added over4 h to a stirred solution of 4,4′-dimethylbenzil (0.48 g, 2.1 mmol) andNH₄OAc (2.43 g, 31.5 mmol) in AcOH (4 mL) at 95° C. The reaction mixturewas allowed to cool to rt, and the solvent was removed under reducedpressure. The residue was purified on silica gel (EtOAc/CH₂Cl₂) toafford the desired imidazole (0.43 g, 49%). HPLC: R_(t)=8.91 (Method C).MS (ESI): mass calculated for C₂₉H₃₀N₂O₂, 438.23; m/z found, 493.3[M+H]⁺.

D. 3-(4,5-Di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acid. To astirred solution of the ester from step C (50.0 mg, 0.11 mmol) in DMF(1.0 mL) was added 2 M LiOH (1.0 mL), and the reaction mixture washeated to 50° C. for 18 h. The mixture was cooled and then purifieddirectly by reversed-phase chromatography (Method B) to afford thedesired acid (41 mg, 91%). MS (ESI): mass calculated for C₂₇H₂₆N₂O₂,410.20; m/z found, 411.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.13 (d, J=8.2Hz, 4H), 6.97 (d, J=8.2 Hz, 4H), 6.97-6.84 (m, 4H), 4.51 (s, 1H), 3.67(t, J=12.0 Hz, 1H), 3.35 (br d, J=12.0 Hz, 1H), 2.23 (s, 6H), 2.10 (s,3H).

Example 31

3-(1-Methyl-4,5-di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acid.

A solution of 3-(4,5-di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionicacid ethyl ester (Example 30, step C; 50 mg, 0.11 mmol), iodomethane (17mg, 0.12 mmol) and K₂CO₃ (79 mg, 0.55 mmol) in DMF (2.0 mL) was stirredand heated to 40° C. overnight. The solvent was removed under reducedpressure, and the crude residue was purified on silica gel(EtOAc/CH₂Cl₂) to give3-(1-methyl-4,5-di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionic acidmethyl ester (13 mg, 26%). The methyl ester (18 mg, 0.042 mmol) washydrolyzed using the conditions outlined in Example 30, step D toprovide the title compound (12 mg, 69% yield). HPLC: R_(t)=2.64 (MethodA). MS (ESI): mass calculated for C₂₈H₂₈N₂O₂, 424.22; m/z found, 425.3[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.28-7.23 (m, 4H), 7.21-7.04 (m, 6H),6.98 (d, J=7.8 Hz, 2H), 4.38 (d, J=9.3 Hz, 1H), 3.54 (dd, J=16.1, 9.3Hz, 1H), 3.22 (dd, J=16.1, 3.1 Hz, 1H), 3.17 (s, 3H), 2.42 (s, 3H), 2.30(s, 3H), 2.27 (s, 3H).

Example 32

3-[4,5-Bis-(2-chloro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionicacid

The title compound was prepared using the methods described in Example30 and Scheme D substituting naphthalen-1-yl-acetic acid ethyl ester form-tolyl-acetic acid ethyl ester in step A, and 2,2′-dichlorobenzil for4,4′-dimethylbenzil in step C (36% yield). HPLC: R_(t)=8.07 (Method C).MS (ESI): mass calculated for C₂₈H₂₀Cl₂N₂O₂, 486.09; m/z found, 487.0[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.11 (br s, 1H), 7.81 (d, J=8.5 Hz,1H), 7.74 (d, J=8.5 Hz, 1H), 7.57-7.38 (m, 3H), 7.32-7.26 (m, 3H),7.24-7.11 (m, 3H), 6.90 (br s, 3H), 5.36 (br s, 1H), 3.93 (br s, 1H),3.74 (s, 1H).

Example 33

3-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionicacid

The title compound was prepared using the methods described in Example30 and Scheme D substituting naphthalen-1-yl-acetic acid ethyl ester form-tolyl-acetic acid ethyl ester in step A, and 3,3′-dimethoxybenzil for4,4′-dimethylbenzil in step C (30% yield). HPLC: R_(t)=8.03 (Method C).MS (ESI): mass calculated for C₃₀H₂₆N₂O₄, 478.19; m/z found, 479.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.11 (d, J=8.1 Hz, 1H), 7.75 (d, J=7.8Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.44-7.28 (m, 3H), 7.13 (t, J=7.3 Hz,1H), 6.96 (t, J=7.3 Hz, 2H), 6.77-6.66 (m, 6H), 5.44 (t, J=6.0 Hz, 1H),3.92 (dd, J=14.9, 9.6 Hz, 1H), 3.69-3.57 (m, 1H), 3.49 (s, 6H).

Example 34

3-[4,5-Bis-(4-fluoro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionicacid

The title compound was prepared using the methods described in Example30 and Scheme D substituting naphthalen-1-yl-acetic acid ethyl ester form-tolyl-acetic acid ethyl ester in step A, and 4,4′-difluorobenzil for4,4′-dimethylbenzil in step C (40% yield). HPLC: R_(t)=8.14 (Method C).MS (ESI): mass calculated for C₂₈H₂₀F₂N₂O₂, 454.15; m/z found, 455.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.14 (br d, J=9.0 Hz, 2H), (br d, J=7.7Hz, 2H), (br d, J=7.7 Hz, 2H), 7.44 (br d, J=27.0 Hz, 2H), 7.16 (br s,2H), 7.04 (br s, 2H), 6.62 (br s, 2H), 5.46 (br s, 2H), 3.81 (t, J=11.3Hz, 2H), 3.50 (br s, 2H).

Example 35

(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylicacid, sodium salt.

To a stirred solution of(Z)-3-[5-benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylicacid (Example 1) in THF (0.2 M) is added aqueous NaOH (1 equiv) at 0° C.The mixture is stirred for 30 min at 0° C. then concentrated to an oilunder reduced pressure using a rotary evaporator (25-30° C.). The oil isdiluted in THF (0.2 M), chilled in an ice bath, and CH₃CN is added toform a precipitate. The suspension is stirred for 2 h, filtered and thenwashed with CH₃CN to afford the title compound.

Assay Method

Cell Culture

CHO-K1 cells that had undergone stable transfection with the CCK-1receptor were grown in DMEM supplemented with L-glutamine (2 mM),penicillin (50 units/mL) and streptomycin (50 μg/mL). Cells werecultured under continuous G418 selection (2 mM) and were harvested usinga rubber cell scraper. CHO-K¹ cells were sub-cultured a maximum of tentimes before being reseeded from the original stocks.

Membrane Preparation

Membranes were prepared from the stably transfected CHO-K¹ cells. Frozencell pellets (−40° C.) were thawed in 14 mL of buffer A (10 mM HEPES,130 mM NaCl, 4.7 mM KCl, 5 mM MgCl, 1 mM EGTA and 15.4 mg/100 mLbacitracin at pH 7.2), adapted from Harper et al. (Br. J. Pharmacol.1996, 118:1717-1726). The thawed pellets were homogenized using aPolytron PT-10 (7×1 s). The homogenates were centrifuged for 5 min at1500 rpm (600×g), and the resulting pellets were discarded. Thesupernatants were re-centrifuged in order to collect thereceptor-membrane pellets (25 min 15,000 rpm; 39,800×g), which werere-suspended in buffer A.

Incubation Conditions

All assays were conducted in 96-well plates (GF/B millipore filterplates) using buffer A, with 0.3 μM PD-134,308, for the dilutions. TheCCK-2 receptor ligand was included to eliminate the contribution of thisreceptor subtype to the binding. For the optimal cell numberdetermination experiments 20 pM [¹²⁵I]-BH-CCK-8S (50 μL 60 pM solution)was incubated with a range of cell concentrations (2.5×105 to 12.5×105cells/well) in a total volume of 150 μL. Total binding of[¹²⁵I]-BH-CCK-8S was determined in the presence of 15 μL of buffer A.Non-specific binding of [¹²⁵I]-BH-CCK-8S was determined in the presenceof 15 μL of 100 μM 2-naphthalenesulphonyl L-aspartyl-(2-phenethyl)amide(2-NAP: see R. A. Hull et al. Br. J. Pharmacol. 1993, 108:734-740), aCCK-1 receptor selective antagonist that is structurally unrelated tothe radioligand [¹²⁵I]-BH-CCK-8S. The assay preparation was incubatedfor 1 h at 21±3° C., and then the assay was terminated upon rapidfiltration of the preparation under reduced pressure. The loaded filterswere washed three times using undiluted PBS (100 μL), and then theresidues were transferred to 5 mL scintillation tubes. Boundradioactivity was determined using a gamma counter (count time=1 min).From these experiments a cell concentration of 1 pellet in 40 mL ofbuffer (2.5×106 cells/mL) was chosen for use in other assays (below). Tovalidate the radioligand concentration and incubation time for theassay, saturation and kinetic binding studies were also conducted (seeM. F. Morton, The Pharmacological Characterization of CholecystokininReceptors in the Human Gastrointestinal Tract. PhD Thesis, University ofLondon, 2000). The affinity of novel compounds was estimated byincubating membrane preparations with 15 μL of competing ligand (0.1pM-1 mM) for 60 min at 21±3° C. The assay was then terminated accordingto the procedure outlined above.

Data Analysis

The pKi values were determined using the equation of Y.-C. Cheng and W.H. Prusoff (Biochem. Pharmacol. 1973, 22(23):3099-3108):

$K_{i} = \frac{{IC}_{50}}{1 + \frac{\lbrack L\rbrack}{K_{D}}}$

To circumvent problems associated with computer-assisted data analysisof compounds with low affinity, the data obtained in the current studywere weighted according to a method described by Morton (2000). Inbrief, 100% and 0% specific binding were defined independently usingtotal binding and binding obtained in the presence of a highconcentration of the reference antagonist, 2-NAP.

TABLE EX pK_(i) 1 8.7 2 8.5 3 8.7 4 8.6 5 8.5 6 8.4 7 8.3 8 8.3 9 8.1 108.0 11 8.0 12 8.3 13 6.7 14 7.0 15 7.1 16 7.1 17 7.1 18 7.2 19 7.8 207.8 21 7.7 22 7.6 23 7.1 24 7.5 25 7.5 26 7.4 27 7.3 28 7.2 29 6.9 307.7 31 7.4 32 6.4 33 5.6 34 5.0

Having described the invention in specific detail and exemplified themanner in which it may be carried into practice, it will be apparent tothose skilled in the art that innumerable variations, applications,modifications, and extensions of the basic principles involved may bemade without departing from its spirit or scope. It is to be understoodthat the foregoing is merely exemplary and the present invention is notto be limited to the specific form or arrangements of parts hereindescribed and shown.

1. A method for the treatment of pancreatic disorder in mammalscomprising the step of administering to a mammal suffering therefrom atherapeutically effective amount of compound having CCK1 antagonist orinverse agonist activity of formula (I):

wherein, R¹ and R² can be the same or different and are selected fromthe group consisting of; a) phenyl, optionally mono-, di- ortri-substituted with R^(p) or di-substituted on adjacent carbons with—OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—,—(CH₂)₂₋₃N(C₁₋₄alkyl)- or —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(p) is selectedfrom the group consisting of —OH, —C₁₋₆alkyl, —OC₁₋₆alkyl, phenyl,—Ophenyl, benzyl, —Obenzyl, —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, —CN,—NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selectedfrom —H, —C₁₋₆alkyl or —C₁₋₆alkenyl, or R^(y) and R^(z) may be takentogether with the nitrogen of attachment to form an otherwise aliphatichydrocarbon ring, said ring having 4 to 7 members, optionally having onecarbon replaced with >O, ═N—, >NH or >N(C₁₋₄alkyl), optionally havingone carbon substituted with —OH, and optionally having one or two doublebonds in the ring), —(C═O)N(R^(y))R^(z), —(N—R^(t))COR^(t),—(N—R^(t))SO₂C₁₋₆alkyl (wherein R^(t) is —H or —C₁₋₆alkyl or two R^(t)in the same substituent may be taken together with the amide ofattachment to form an otherwise aliphatic hydrocarbon ring, said ringhaving 4 to 6 members), —(C═O)C₁₋₆alkyl, —(S═(O)_(n))—C₁₋₆alkyl (whereinn is selected from 0, 1 or 2), —SO₂N(R^(y))R^(z), —SCF₃, halo, —CF₃,—OCF₃, —COOH and —COOC₁₋₆alkyl; b) phenyl or pyridyl fused at twoadjacent ring members to a three membered hydrocarbon moiety to form afused five membered aromatic ring, which moiety has one carbon atomreplaced by >O, >S, >NH or >N(C₁₋₄alkyl) and which moiety has up to oneadditional carbon atom optionally replaced by N, the fused ringsoptionally mono-, di- or tri-substituted with R^(P); c) phenyl fused attwo adjacent ring members to a four membered hydrocarbon moiety to forma fused six membered aromatic ring, which moiety has one or two carbonatoms replaced by N, the fused rings optionally mono-, di- ortri-substituted with R^(P); d) naphthyl, optionally mono-, di- ortri-substituted with R^(P); e) a monocyclic aromatic hydrocarbon grouphaving five ring atoms, having a carbon atom which is the point ofattachment, having one carbon atom replaced by >O, >S, >NH or>N(C₁₋₄alkyl), having up to one additional carbon atoms optionallyreplaced by N, optionally mono- or di-substituted with R^(P) andoptionally benzo fused, where the benzo fused moiety is optionallymono-, di- or tri-substituted with R^(P); and f) a monocyclic aromatichydrocarbon group having six ring atoms, having a carbon atom which isthe point of attachment, having one or two carbon atoms replaced by N,having one N optionally oxidized to the N-oxide, optionally mono- ordi-substituted with R^(P) and optionally benzo fused, where the benzofused moiety is optionally mono- or di-substituted with R^(P); R³ isselected from the group consisting of —H and —C₁₋₆alkyl; m is selectedfrom 0, 1, or 2; Ar is selected from the group consisting of: A) phenyl,optionally mono-, di- or tri-substituted with R^(r) or di-substituted onadjacent carbons with —OC₁₋₄alkyleneO—, —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—,—(CH₂)₂₋₃N(C₁₋₄alkyl)- or —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—; R^(r) is selectedfrom the group consisting of —OH, —C₁₋₆alkyl, —OC₁₋₆alkyl, phenyl,—Ophenyl, benzyl, —Obenzyl, —C₃₋₆cycloalkyl, —OC₃₋₆cycloalkyl, —CN,—NO₂, —N(R^(a))R^(b) (wherein R^(a) and R^(b) are independently selectedfrom —H, —C₁₋₆alkyl or —C₁₋₆alkenyl, or R^(a) and R^(b) may be takentogether with the nitrogen of attachment to form an otherwise aliphatichydrocarbon ring, said ring having 4 to 7 members, optionally having onecarbon replaced with >O, ═N—, >NH or >N(C₁₋₄alkyl), optionally havingone carbon substituted with —OH, and optionally having one or two doublebonds in the ring), —(C═O)N(R^(a))R^(b), —(N—R^(c))COR^(c),—(N—R^(c))SO₂C₁₋₆alkyl (wherein R^(c) is H or C₁₋₆alkyl or two R^(c) inthe same substituent may be taken together with the amide of attachmentto form an otherwise aliphatic hydrocarbon ring, said ring having 4 to 6members), —(C═O)C₁₋₆alkyl, —(S═(O)_(q))—C₁₋₆alkyl (wherein q is selectedfrom 0, 1 or 2), —SO₂N(R^(a))R^(b), —SCF₃, halo, —CF₃, —OCF₃, and—COOC₁₋₆alkyl; B) phenyl or pyridyl fused at two adjacent ring membersto a three membered hydrocarbon moiety to form a fused five memberedaromatic ring, which moiety has one carbon atom replaced by >O, >S, >NHor >N(C₁₋₄alkyl) and which moiety has up to one additional carbon atomoptionally replaced by N, the fused rings optionally mono-, di- ortri-substituted with R^(r); C) phenyl fused at two adjacent ring membersto a four membered hydrocarbon moiety to form a fused six memberedaromatic ring, which moiety has one or two carbon atoms replaced by N,the fused rings optionally mono-, di- or tri-substituted with R^(r); D)naphthyl, optionally mono-, di- or tri-substituted with R^(r); E) amonocyclic aromatic hydrocarbon group having five ring atoms, having acarbon atom which is the point of attachment, having one carbon atomreplaced by >O, >S, >NH or >N(C₁₋₄alkyl), having up to one additionalcarbon atoms optionally replaced by N, optionally mono- ordi-substituted with R^(r) and optionally benzo fused on the conditionthat two or fewer of said carbon ring atoms are replaced by aheteroatom, where the benzo fused moiety is optionally mono-, di- ortri-substituted with R^(r); and F) a monocyclic aromatic hydrocarbongroup having six ring atoms, having a carbon atom which is the point ofattachment, having one or two carbon atoms replaced by N, optionallymono- or di-substituted with R^(r) and optionally benzo fused, where thebenzo fused moiety is optionally mono- or di-substituted with R^(r); R⁴is selected from the group consisting of; I) —COOR⁵, where R⁵ isselected from the group consisting of —H and —C₁₋₄alkyl, and II)—CONR⁶R⁷, where R⁶ and R⁷ are independently selected from the groupconsisting of —H, —C₁₋₆alkyl and —C₃₋₆cycloalkyl optionally hydroxysubstituted, or R⁶ and R⁷ may be taken together with the nitrogen ofattachment to form an otherwise aliphatic hydrocarbon ring, said ringhaving 5 to 7 members, optionally having one carbon replaced with >O,═N—, >NH or >N(C₁₋₄alkyl) and optionally having one or two double bondsin the ring; and enantiomers, diastereomers, and pharmaceuticallyacceptable salts, esters and amides thereof.
 2. The method of claim 1wherein the compound of formula 1 is selected fromthe group consistingof:(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylicacid;(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylicacid;(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylicacid;(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-acrylicacid;(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(4-chloro-phenyl)-acrylicacid;(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylic acid;(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylicacid;(Z)-2-(3-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H -imidazol-2-yl]-acrylic acid;(Z)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylic acid;(Z)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylicacid;(Z)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylic acid;(Z)-2-(3-Chloro-phenyl)-3-(5-naphthalen-2-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-acrylicacid; and(E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-acrylicacid.
 3. The method of claim 1 wherein the compound of formula 1 isselected from the group consisting of:(E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylic acid;(E)-2-(4-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H -imidazol-2-yl]-acrylic acid;(E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylicacid;(E)-3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylic acid;(E)-2-(3-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H -imidazol-2-yl]-acrylic acid;(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichioro-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-acrylicacid;(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(4-chloro-phenyl)-acrylicacid;(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichioro-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-acrylicacid; and(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichioro-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-acrylic acid.
 4. The method of claim 1 wherein the compound offormula 1 is selected from the group consisting of:(E)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-acrylicacid;3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-m-tolyl-propionic acid;2-(3-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-propionic acid;3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionic acid;3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-(3-trifluoromethyl-phenyl)-propionic acid;2-(4-Chloro-phenyl)-3-[4-(3,4-dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-propionic acid;3-[4-(3,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-1H-imidazol-2-yl]-2-p-tolyl-propionic acid; 3-(4,5-Di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionicacid; 3-(1-Methyl-4,5-di-p-tolyl-1H-imidazol-2-yl)-2-m-tolyl-propionicacid;3-[4,5-Bis-(2-chloro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionicacid;3-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionicacid;3-[4,5-Bis-(4-fluoro-phenyl)-1H-imidazol-2-yl]-2-naphthalen-1-yl-propionicacid; and(Z)-3-[5-Benzo[1,3]dioxol-5-yl-4-(2,5-dichloro-phenyl)-1H-imidazol-2-yl]-2-(3-chloro-phenyl)-acrylicacid, sodium salt.